Comprehensive Guide To Schizophrenia 

Clinical phenomenology is the basis for diagnosing and characterizing schizophrenia.

Benedict Morel

Benedict Morel documented his observations on specific patients. The characteristics of schizophrenia match those descriptions. Demence Precoce is a phrase he created. 

Emil Kraeplin (1856-1926)

Emil Kraeplin invented the term "psychiatric nosology" and made a significant contribution to the field of schizophrenia. He split and segregated the wide category of psychosis into two groups:
He created the term Dementia Praecox. The first category is organic psychosis, which encompasses conditions like syphilitic insanity and general paresis. 

The second category is primary or functional psychosis. Praecox denotes an early onset, and dementia denotes a deterioration in cognition. When dementia or cognitive changes are discussed, it is important to note that these patients no longer exhibit inner unity in their mental, emotional, or volitional activity. He separated the two main forms of functional psychotic disorders:
1. Praecox dementia
2. Manic depressive psychosis. He distinguished between the two on the basis of the illness's trajectory and long-term prognosis. 

The course of dementia praecox will be constant, irreversible, and deteriorating. Manic depressive psychosis patients will experience an episodic, non-deteriorating course of illness. Praecox dementia is characterized by flare-ups and remissions. It would follow an ongoing, downward trajectory. A full recovery would never occur. 

Manic-depressive psychosis would progress in episodes, with the patient recovering fully in between. Manic depressive psychosis belongs to the category of bipolar illness, whereas dementia Praecox is under the category of schizophrenia. Emil Kraeplin introduced the subcategories; some of these subtypes, which at the time were recognized as distinct entities, were combined to form dementia praecox. Hebephrenic, catatonic, and paranoid are a few of the subtypes. 

Eugene Bleuler

He first used the term "schizophrenia" in 1911. Phrenia means mind, and schizo means split. Splitting of psychic functions is a sign of schizophrenia. When the psychic functions split, the patient's thoughts, feelings, and behavior no longer coordinate harmonically. 

He also discussed the signs of schizophrenia, identifying two different kinds of symptoms: Initial signs and symptoms and secondary indications Bleuler's four As are another name for the primary symptoms of schizophrenia: Aberrant associations, Aberrant affect, Autistic behavior and thought, and ambivalence (inability to decide) are the four main symptoms. Delusions, hallucinations, social disengagement, and decreased drive are examples of secondary symptoms. 

Kurt Schneider

Schneider identified what are referred to as Schneider's first-rank symptoms (SFRS), which are indications of schizophrenia.
When none of these conditions were present—intoxication, brain damage, or mental illness—he described having one of these symptoms.

These 11 SFRS Symptoms Are:

Schneider’s First Rank Symptoms (SFRS)

1. Audible Thoughts/ Thought ECHO
2. Voices Discussing about Pt.
3. Voice commenting on one’s Action/ Running commentary
4. Thought Insertion
5. Thought withdrawal
6. Thought Broadcast
7. Made Impulses
8. Made Feelings
9. Made Acts
10. Somatic Passivity
11. Delusional Perception

Auditory Hallucinations

Thought Echo or Audibility: The patient is able to hear his own thoughts.
Arguments or discussions between voices: The patient may report hearing and seeing two or more voices having a conversation.
Voices offering running commentary or remark on an action.

Thought Phenomenon

Thought Insertion: The patient may state, "I have some thoughts, but someone else inserted them."  Thought withdrawal: The patient could feel as though some ideas are being removed from his consciousness.
Thought broadcast: When someone experiences thought broadcast, they feel as though their thoughts are being shared with others. 

Made Impulses

The patient feels that other people have an impact on his emotions, impulses, and actions.  Created drives/impulses,  Created emotions.
Performed deliberate acts.

Somatic Passivity

The patient has visceral or tactile hallucinations that are imposed by an outside source when they are in somatic passivity. It might be a synthesis of several somatic experiences. It's possible that the patient is merely a passive recipient of bodily experiences that are imposed by outside forces. For instance, a patient reports that radiowaves from extraterrestrials are the cause of his stomach ache. In a another instance, someone can claim that his neighbor's black magic is to blame for his headache. 

Delusional Perception

A perception that gives rise to an instantaneous, irrational interpretation due to its distinct and peculiar significance for each individual.  Delusional meaning to it coexists with normal perception. For instance, it's common for someone to perceive that their spouse wants to kill him when they see her wearing a red and white saree. However, this is not the case in this scenario. 

Primary Delusion: It doesn't stem from any other pathological phenomenon; rather, it is a direct manifestation of an underlying disease.  Secondary delusion: This type of delusion arises from other severe psychological symptoms or occurrences. 

Ernst Kretschmer

He discovered that individuals with dysplastic, athletic, slim, or beautiful builds had a higher risk of developing schizophrenia compared to Pyknic (short, stocky, robust) individuals, who are more likely to experience bipolar disorder.

Karl Jaspers

In order to comprehend the psychological significance of delusions and hallucinations, two common symptoms of schizophrenia, Karl Jaspers conducted extensive research on the phenomenology of mental disease. 

Epidemiology

The DSM 5 states that the lifetime prevalence of schizophrenia is between 0.3 and 0.7% based on current research. About 0.7% of people globally will have schizophrenia in their lives. The DSM-IV TR states that the lifetime prevalence was 1% earlier. The National Institute of Mental Health's catchment area survey found that between 0.6 and 1.9% of people had schizophrenia.

Males and females are almost equally affected by schizophrenia.
Males typically experience the onset of schizophrenia between the ages of 10 and 25. The distribution of this peak age in females is bimodal. In females, the age at which schizophrenia start occurs peaks between 25 and 35 years of age, and another peak happens after 40 years of age. Males typically have a worse prognosis than females when it comes to health. 

Late-onset Schizophrenia: This type of schizophrenia is defined as having started after the age of 45. Early onset schizophrenia: This includes both adolescent and juvenile onset forms of the disease. It happens before the age of eighteen. It may be associated with serious brain abnormalities, a poor psychosocial functioning, and a severe clinical course. Schizophrenia with a childhood onset: It manifests before the age of thirteen. 

Etiology

Genetic Factors

Studies on population epidemiology, families, twins, adoption, linkage, and association are conducted in the area of genetic variables.  GWA investigations, sequence studies, and copy number variation are now included in the image. 

Population epidemiology studies

The prevalence in the general population is one percent.  Siblings who are not twins are at 8% risk.  The risk is 12% for a child who has a dizygotic twin and one parent who has schizophrenia.  The chance of schizophrenia in a kid whose two parents have the disorder is 40%, while the risk in monozygotic twins is 47%.

Family Studies

According to family studies, probands' relatives are more likely to have the condition. This was Ernst Rudin's first systemic study (1916).
Some patients' relatives are more at risk than others.

Heritability

About 81% of cases of schizophrenia are heritable, compared to 85% of cases of bipolar disorder. Twin studies and adoption studies are conducted in order to verify if the cause is due to genetic factors or shared environment. 

Twin Studies

Concordance rates between monozygotic and dizygotic twins are compared in twin studies.  The concordance rate is 10% for dizygotic twins and 50% for monozygotic twins.  In monozygotic disorders, concordance rates are less than 100%, indicating that environmental factors in addition to genetic factors are crucial in the development of the condition. 

The concordance rate can be found using one of two methods:
1. The pairwise approach
2. Proband-by-proband technique

By taking the concordance pair over the total number of twin pairs, we can determine the concordance rate using the pairwise technique. Suppose there are ten pairs of twins. Of them, five have schizophrenia in both twins, and the other five have schizophrenia in one twin. Thus, concordance pairings/total twin pairs, or 5/10, are computed. Thus, 50% would be the pairwise concordance rate. 

In determining the proband-wise approach, each of the two participants was determined separately. The number of impacted co-twins divided by the number of probands is how it is determined. Geneticists favor the proband approach, which indicates the likelihood that the twins of a person with schizophrenia will also develop the illness. 

Also Read: Dysthymic Disorder Criteria And Clinical Features

Why Is There Discordance For A Heritable Disorder In Monozygotic Twins?

Both twins received the same genetic liability, but only the affected twin expresses it. Affected twin has phenocopy, or a form of the disease that is influenced by the environment. 

Shortcomings Of The Twin Method

Children and their parents and siblings share the same environment and DNA. Therefore, it is challenging to determine whether environmental or genetic factors are to blame.

Adoption Studies

Studies on adoption are conducted in order to regulate the external influences. Two studies on adoption exist:  Research on cross-fostering
Studies on adoptive families 

Research on Cross-Fostering: There are two scenarios: the first involves typical parents and their offspring, and the second involves individuals with schizophrenia and their offspring. Environmental considerations are considered and these two child groups are cross-fostered. 

Adoptive Family Studies: A kid born to parents suffering from schizophrenia is adopted shortly after, and raised by parents free of schizophrenia.

General Principles Of Adoption Studies

In the event that the disorder has a genetic component, adopted children and their biological parents should have more in common than adopted children and their adoptive parents.  The risk is similar to those reported among children of parents with schizophrenia seen in family studies, suggesting most familial transmission is genetic.

 Children of parents with schizophrenia who are adopted away very soon after birth have a 10% chance of developing schizophrenia, schizoaffective disorder, or other narrow-spectrum schizophrenic disorder. 

Does Schizophrenia Breed True?

It was once thought that bipolar disorder and schizophrenia mostly breed one another. However, there are families with members who suffer from bipolar disorder, schizophrenia, or both psychosis and mood disorders. Additionally, twin studies reveal that relatives of probands with schizophrenia also have additional problems. 

Also Read: Glutamic Acid: Synthesis, Pathways, Receptors, Uses And Conditions

Strategies To Find Specific Genes That Cause Schizophrenia 

Linkage Studies

It is more useful to find genes causing Mendelian disorders. Genotyping families with hundreds of highly informative markers (microsatellites) spread over the genome at approximately equal distances. Linkage studies have concluded there is no single gene for schizophrenia, it is not a single-gene disorder. Different linkage findings suggest different genes operate in different populations. Schizophrenia is caused by the effect of many genes of small effect so sometimes studies have no power to detect loci. 

Association Studies

It is positive linkage studies followed by fine mapping association studies of genes in linked chromosomal regions.

Genome-Wide Association Studies

It is done to identify the candidate gene studies.

1. The dysbindin gene (DTNBP1) is located on chromosome 6p22.3. Both the DLPFC and the hippocampal regions express dysbindin. The beta DYSTOBREVIN-binding protein dysbindin is crucial for synaptic signaling and structure.  Changes in DTNBP1 modify presynaptic glutamate function, which raises the risk of schizophrenia.
2. Neuroregulin (NRG1) Neuroglia are members of the growth factor family and are found on 8p 21–22. It is critical for neurotransmission, neuronal migration, and synapse formation. 
3. Disc 1, (disrupted in schizophrenia)
   • The translocation of chromosomes (1 to 11) is balanced (q 42 and q 14.3). It has an impact on intracellular transport, neuronal architecture, and neural migration. It is associated not just with schizophrenia but also with recurrent depression and bipolar illness. 
4. DAOA (G72) 
   • This gene codes for a protein that activates the DAO enzyme, which breaks down the co-transmitter D serine and again affects the NMDA receptor's glutamate neurotransmission. 
5. RGS4 
   • It affects metabotropic glutamate receptor signaling and is a modulator of G protein signaling. 
6. GRM3 (metabotropic glutamate) 
7. The metabolism of monoamines is connected to the COMT gene, also known as catechol o methyl transferase. 
8. Nicotinic receptors, alpha 7 (CHRNA7)
   • Synaptic plasticity and glutamatergic neurotransmission may be linked to a few of the genes.
   • Genes linked to neuregulin, like as glutamate or GABA, or acetylcholine, like CHRNA7 and RGS4, may be identified. Dopamine and serotonin, as well as NMDA receptor hypofunction, may all be impacted by RGS4. It could result in dysregulation of AMPA-R, inappropriate long-term potentiation, abnormal synaptic plasticity, synaptic elimination, and weak synapses. 

Copy Number Variations

These are chromosomal duplications and deletions that are at least one kilobase in size. 

The Syndrome of Chromosome 22q11.2 Deletion

DiGeorge or velocardiofacial syndrome are other names for it. The deletion syndrome is where it is most prevalent. There is a higher chance that they will experience more psychotic disorders. 

NRXN1

There is only one gene involved. Neurexin 1 (cell adhesion molecule) is encoded by it. At synapses, it is involved in the synthesis, upkeep, and release of neurotransmitters. Carriers of certain CNVs are even more likely than schizophrenia to suffer an early onset disorder (such as ASD, developmental delay, or congenital). There could be a 40% penetration rate.

Sequencing Studies 

They assist in the detection of minor and rare variants, single nucleotide variants (SNVs), and small insertions and deletions (indels). • They employ exome sequencing, which involves sequencing every exon in the genome.  Additionally finds de Novo mutations.

Genetics in Schizophrenia

Allelic risk exists on a spectrum.  While the effective amount of common genes in a population is usually small, they account for one-third of genetic liability.  Rarer alleles might exist, and some of them might significantly impact a person's likelihood of contracting a disease. 

Also Read: Limbic System: Structure, Function, Embryology And Clinical Significance

Neurobiological Factors

Neuroanatomical Factors

Enlarged cerebral ventricles are a recurrent observation in patients with schizophrenia; nevertheless, this enlargement is not precise enough to be diagnosed. The cortical volume (grey matter) is decreasing.  The limbic system appears to be impacted in people with schizophrenia; there may be structural abnormalities such as a decrease in the size of the hippocampus, amygdala, and parahippocampal gyrus. There is diminished symmetry in brain areas including the temporal, frontal, and occipital lobes. Functional anomalies could exist, for example, disruptions in glutamate transmission in the hippocampus. 

There may be a decrease in volume and visible functional abnormalities in the prefrontal cortex.  The thalamus is shrinking; in particular, the neurons in the medial dorsal nucleus of the thalamus may have shrunk by 30 to 45%.  The globus pallidus and substantia nigra, two regions of the basal ganglia, are shrinking in size. The size of the caudate putamen complex has increased. The outcomes have been inconsistent. D2 receptors in the caudate, putamen, and nucleus accumbens are increased.

Localization of Symptom Domain

Disruptions to the mesolimbic circuit may be linked to positive symptoms of schizophrenia.  The mesocortical circuit is the cause of negative symptoms.  Dorsolateral PFC will exhibit cognitive signs.  The orbitofrontal cortex and amygdala of schizophrenia can also exhibit aggressive signs.  Ventromedial PFC may be associated with affective symptoms.

Neuropathological Changes

These can be comprehended by using a microscope to examine post-mortem human brain tissue.  The brain seems normal when viewed macroscopically with the unaided eye.  The brain's post-mortem weight decreases and has an inverse relationship with the age at onset. * People with prodome, first-break psychosis, and persistent illnesses had reduced brain sizes. 

The thalamus, medial temporal lobe, and prefrontal cortex (PFC) are the regions most associated with alterations in cellular morphology.
The primary location of malfunction is the PFC; there is a deficiency in neural connections rather than a neuronal count. Dendritic spine density is observed to be declining in layer 3 of PFC, which is associated with Brodmann areas 9 and 46.

Medication is not the cause of it. Schizophrenia patients have less spine density when comparing their dendritic spines to those of normal persons. The primary location for integrating data from the thalamus and other cortical neurons is Layer 3, which is made up of pyramidal neurons. 

In terms of hippocampus development, patients with significant hereditary loading of the disease and those at the beginning of sickness exhibit small hippocampal volumes. They might move to the left side lateralization. 

Anterior-posterior gradients are observed in the neuropathological results, and in the apical dendrite, dendritic spine density is decreased in the subiculum and elevated in the CA3 pyramidal cell.

Thalamus: Neuron density decreases in the thalamic mediodorsal nucleus.  Basal ganglia: The volume of the caudate putamen complex has increased, although the results are not entirely consistent.
Genes related to the oligodendrocyte pathway, myelin-associated glycoprotein, and oligodendrocyte transcription factors are all downregulated in white matter alterations. NRG1 and DISC1 are two genes linked to myelin and oligodendrocyte activity. 

Neurotransmitters

According to the dopamine hypothesis, individuals with schizophrenia have higher levels of dopamine. This theory was based on two observations: the first was the effectiveness of antipsychotic medications, and the second was the psychomimetic nature of substances like cocaine that raise dopamine levels.  There are two key dopaminergic pathways.
1. Mesolimbic Route: This pathway travels from the ventral tegmental area of the midbrain to the limbic system and ultimately the nucleus accumbens. There is an increase in dopamine in this route.
2. Mesocortical Pathway: It connects the prefrontal cortex, a cortical region, to the ventral tympanic arch. The dopamine in this route is declining.

Serotonin

Serotonin is also involved; positive and negative symptoms of schizophrenia are observed to be caused by an increase in serotonin in these people. 

Glutamate 

Glutamate may cause neurotoxicity, hypoactivity, or hyperactivity. Schizophrenia patients exhibit NMDA hypofunction, and many NMDA antagonists, including PCP and ketamine, cause psychotic symptoms. During the postnatal neurodevelopmental process, the juvenile NMDA-R subunit Glu N2B changes to the adult NMDA-R subunit Glu N2A. Certain early environmental stressors are observed to hinder this transformation in animal models. Schizophrenia also inhibits this transition.

Norepinephrine

Patients with schizophrenia experience a loss of norepinephrine neurons. It has been linked to adverse effects like anhedonia.  The hippocampal region is losing GABAergic neurons. GABA regulates dopamine in an action.  Dopamine neurons become hyperactive when GABA is lost.

Acetylcholine

The symptoms related to cognition are impacted by the loss of cholinergic neurons. Catecholamine and indolamine neurotransmitters are localized with neuropeptides such substance P and neurotensin.

Also Read: 5 Effective Study Strategies for Psychiatry Residency Exams

Electrophysiology

1. EEG

Records that are unusual are observed. They are more susceptible to activation processes, as seen by the numerous spikes in activity that follow sleep deprivation. The alpha activity is declining. The activity of θ or λ is increasing. Schizophrenia patients are highly sensitive to background noise and are unable to block out extraneous sounds.

2. Evoked Potential

Schizophrenia patients' evoked potentials show a great deal of anomalies. P 300 is the most researched evoked potential. It is a sizable wave of positive evoked potential that is noticed 300 milliseconds following a sensory stimulation. The limbic system structure of the medial temporal lobes is the primary source of this P300. P300 is observed to be statistically smaller in schizophrenia patients compared to the reference group. Children who are at a high risk of developing schizophrenia also frequently exhibit abnormalities in the P300 wave. N 100 is another anomaly in the evoked potential. A negative wave known as N 100 happens 100 milliseconds following a stimulus.

There is a slow-developing negative voltage shift in the contingent negative variation, which is another anomaly. Smaller late evoked potentials show that, although individuals with schizophrenia are typically sensitive to sensory stimuli, they compensate for this heightened sensitivity by blunting the processing of information at higher cortical levels. 

3. Eye Movement Dysfunction

Accurately following a moving visual target is impossible.  Disinhibition of saccadic eye movements and aberrant smooth visual pursuit eye movements are observed. 

Smooth Pursuit Eye Movement Abnormality

Smooth pursuit eye system helps in maintaining an image of a small moving object intersecting within sensitive parts of the retina and fovea. • When an object intersects and starts moving, there is slippage of its image on the retina away from the fovea. • Reflexively there is stimulating smooth pursuit initiation response within 135-150 milliseconds. 

Abnormalities in the smooth pursuit eye movement can be observed during the beginning and maintenance phases. The negative symptoms of schizophrenia patients may be associated with the initiation phase, and relatives of patients with schizophrenia may also exhibit maintenance abnormalities. 

Disinhibition Of Saccade Eye Movement

Rapidly shifting attention to bring a new target onto the fovea is facilitated by saccadic eye movements.  Approximately 50–80% of schizophrenia patients may exhibit these anomalies. About 25% of mental health patients do not have schizophrenia. About 10% of patients lack mental control. 

4. Neural Synchronization Deficits

Binding is the process by which sensory information from many modalities and cortical areas is integrated. • At the cellular level, information processing involves tonic or phasic electrical firing of neurons, which is frequently coordinated. A cohesive perceptual experience is the outcome of this. Narrow-band oscillations in the gamma frequency range of 30-80 hz mediate this synchronization.  Schizophrenia symptoms are associated with decreased gamma band synchronization. Positive symptoms such as visual hallucinations could be associated with it. Additionally, it may be linked to concentration problems, disorganization, and thinking disorders. 

5. Sensory Gating (P50) Deficit

Sensory gating is the blocking of a neuron's response to a redundant sensory input by central mediation. Schizophrenia reduces this inhibition.  P50 is the little increase in electoral potential that occurs 50 milliseconds following the stimulus presentation. 

If the two stimuli are connected, a positive wave typically appears 500 milliseconds apart, 50 milliseconds following stimulus S2. The decreased S2 indicates that the second stimulus has inhibited the neural responses.  S2 P50 amplitude is compared to S1 P50 amplitude in sensory gating. 

When a novel stimulus (S1 in P50 gating) is processed initially, oscillation in gamma frequency (peaking in 50 ms) is involved, then after around 120 ms, oscillation in the beta range takes place.  Evidence of P50 sensory gating phenotype may be correlated with chr 15q14 and also correlated with the promotor region of alpha nicotinic cholinergic receptor unit (15q locus). This gamma to beta switch, specifically post S1 beta frequency response, predicts S2 suppression in patients with schizophrenia.

6. Prepulse inhibition

In the presence of a preceding weak sensory signal (prepulse such as noise), the initiated reflex is typically repressed or muted in response to a powerful stimulus (loud noise). This is a malfunction of sensorimotor gating.  It manifests as prepulse, which happens 30 to 500 ms prior to the pulse triggering the startle reflex. 

The brain uses this technique to filter or gate out ambient noise so that important environmental elements may be processed. Schizophrenia patients and their family did not exhibit the typical prepulse suppression of the startle response. Moreover, dopamine may control sensorimotor gating. 

Psychoneuroimmunology

Patients diagnosed with schizophrenia are linked to certain anomalies in their immune response.
• The generation of interleukin 2 by T cells is declining.
Peripheral lymphocytes are becoming fewer in number and less sensitive.
Anomalies include aberrant humoral and cellular responses to neurons.
• Brain-specific antibodies are present.
• Psychosis can result from a number of autoimmune disorders. lupus encephalitis, for instance.
• Psychotic sickness can result from some immunological encephalitis types, such as anti-NMDA receptor encephalitis. 

Psychoneuroendocrinology

There is a drop in LH and FSH hormones connected with age of onset and duration of disease; these abnormalities are in addition to abnormal dexamethasone suppression test results in patients with schizophrenia.
Two anomalies that are associated with adverse symptoms are: Abrupt release of growth hormone and prolactin upon stimulation by GRH or TRH; Abrupt release of GH upon stimulation by apomorphine.

Also Read: Nymphomania: Causes, Symptoms, Risk Factors, Diagnosis, Treatment

Environmental And Other Factors

Risk Factors Occurring During Early Development

• Paternal age: Children born to fathers over 50 at the time of conception have a three to four times higher risk of developing schizophrenia. Growing older fathers have been linked to an increase in de novo mutations in GERM cells as well as disruptions in DNA methylation and gene expression.
• Season of birth: Winter birth, particularly in the northern hemisphere, is significantly associated with the later onset of schizophrenia. Urban births appear to have a stronger effect than rural ones. Two theories are being considered: the first is the possibility of exposure to intrauterine viral infection during the period of pregnancy; the second is the possibility of variations in light, temperature, weather, or environmental pollutants. 

Complications related to pregnancy and delivery: If there are anomalies in the growth and development of the fetus, such as small head circumference, low birth weight, or congenital abnormalities. pregnancy-related issues such hemorrhage, diabetes, pre-eclampsia, or Rh incompatibility. birth complications include emergency cesarean sections, uterine atony, and hypoxia. 

Other Prenatal Factors

• Infections
• Contracting influenza when expecting a child.  Exposure to diseases during pregnancy, including poliovirus, toxoplasmosis, rubella, and other common respiratory illnesses.  Pregnancy-related stress, rhesus incompatibility, and dietary deficiencies may cause schizophrenia. 

Risk Factors During Childhood And Adolescence

Urban birth and upbringing: The danger is twice as high in urban environments as it is in rural ones. Prior to beginning, urban exposure is more significant than the time of onset. The most important fifteen years are the first fifteen. Social dynamics that may occur at the neighbourhood level and influence the risk of schizophrenia include ethnic density. 

Migration: The prevalence of schizophrenia is rising among migrants, particularly among those who are second generation born in a new country. Negative social experiences and potential gene-environment interactions could exist. 

Cannabis use: Using cannabis before increases the risk of developing schizophrenia and psychosis later on. There is some indication that some polymorphisms could potentially mitigate this correlation.

When exposed to cannabis, those homozygous for the COMT valine variant are more likely to develop schizophrenia than those with the methionine allele. Stressful life events and early childhood trauma: Those who experience early childhood trauma, as well as physical, sexual, emotional, and neglect, are at a higher risk. 

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